The RNA polymerase of influenza viruses contains a cap-dependent endonuclease domain that cleaves host mRNAs to produce capped RNA fragments to serve as primers for initiating viral mRNA synthesis.
Translation of viral mRNAs by host ribosomes requires that the viral mRNAs be 5′-capped. This is achieved in cells infected with influenza viruses by a “cap-snatching” mechanism in which the cap-dependent endonuclease cleaves 5′-caps from host mRNAs, which are then utilized as transcription primers (10-13 nucleotides). These capped RNA primers are used for synthesizing mRNAs encoding viral proteins.
Inhibiting the activity of cap-dependent endonuclease results in suppression of virus proliferation. As such, the cap-dependent endonuclease is a potential biological target for identifying effective anti-influenza agents.
Various heterocyclic compounds have been used as cap-dependent endonuclease inhibitors. Yet, conventional heterocyclic compounds exhibit poor pharmacological properties, e.g., poor efficacy, low solubility, and poor bioavailability, thereby rendering them impractical for use as therapeutics for treating influenza.
There is a need to develop new cap-dependent endonuclease inhibitors for treating influenza that do not suffer from the above-described drawbacks.